The subject of the present invention is the use of preparations based on chondroitin sulfate and chitosan for the preparation of compositions intended for the prevention or treatment of rheumatic conditions and, in particular, degenerative arthropathies, by the general route.
The joints and the various connective tissues of which they consist (cartilages, fibrocartilages, synovial membranes, ligaments and the like) are constantly subjected to mechanical stresses and to stresses which may lead to inflammatory pathologies such as arthritis or degenerative pathologies such as osteoarthritis, which are responsible for their blockage. These conditions may be acute at the level of the joints in the neck, the shoulders, the back, the hips, the forelimbs such as the elbows and the wrists, the hindlimbs such as the knees and the ankles, as well as the fingers or the toes. These pathologies are very frequent and affect both humans and animals.
Mainly two families of antiinflammatory compounds are used in human and veterinary rheumatology: the glucocorticosteroids and the NSAIDs (or nonsteroidal anti-inflammatory drugs: salycilates, indoles and related compounds, propionics, pyrazoles, anthranylines and the like). Although relieving pain and reducing the inflammatory state of connective tissues during their use, these compounds have only a pain-relieving function and do not allow a return to the normal state by the reconstitution of the tissues. Thus, these treatments are in the long term ineffective, or even harmful, because they block the natural processes for the defence of the body and lead to a destruction of the connective tissues.
When they are subjected to exercise, stress and in particular when they are the seat of lesions, the connective tissues naturally produce large quantities of collagen and of proteoglycans (PG), which are major components of these tissues, so as to become reconstituted.
These compounds, as well as their mechanisms of biosynthesis and of action, are perfectly known and described in the literature.
Collagen is manufactured from amino acids, in particular from proline, glycine and lysine, and its biosynthesis is stimulated by the presence of glucosamine.
Proteoglycans, which are large macromolecular complexes, for their part, consist of modified long chains of sugars called glycosaminoglycans (GAG) such as hyaluronic acid, chondroitin sulfates or alternatively heparin, and of which glucosamine is a precursor.
In the processes for the reconstitution of connective tissues, collagen and proteoglycans form a matrix which confers on the tissues their mechanical properties. However, the processes for the in vivo biosynthesis of collagen and of proteoglycans from precursor molecules are relatively long, which constitutes an impediment to the repair of these tissues.
Accordingly, to promote the reconstitution of the connective tissues, some treatments consist in bringing exogenous precursor molecules into the body.
Thus, it has been proposed, in U.S. Pat. No. 5,145,841, to treat rheumatic conditions of an inflammatory nature and, in particular, arthritis, by injecting, either directly into the tissues where the inflammation exists, or into the general circulation (by the intramuscular, subcutaneous or intravenous route), compositions comprising at least two compounds chosen from hyaluronic acid, corticoids and sulfated polysaccharides of the heparin sulfate and chondroitin sulfate type, the latter being preferably used in the form of complexes with a metal ion.
Moreover, U.S. Pat. No. 5,364,845 and No. 5,587,363 as well as European patent application No. 0 693 928 describe compositions intended for the protection and repair of the connective tissue, which are, for their part, intended to be administered by the oral route and which consist of combinations between an amino sugar and a glycosaminoglycan with optionally a manganese salt. The amino sugar is chosen from glucosamine, its salts and mixtures thereof, while the glycosaminoglycan is chosen from chondroitin sulfates, their salts and mixtures thereof.
Although these combinations have shown a synergistic effect compared with compositions containing either glucosamine alone, or chondroitin sulfate alone, it is known that the exogenous molecules thus provided to the body and, in particular, the chondroitin sulfates and their salts, are substantially degraded in vivo. This degradation reduces the quantity of precursor molecules capable of being used for the reconstruction of the connective tissue and, consequently, the expected therapeutic benefit, in particular in the case where these molecules are administered by the oral route.
It is therefore desirable to have compositions with enhanced therapeutic efficacy.
Chitosan is a polysaccharide which is obtained by a more or less total N-deacetylation of the chitin. The hydrolysis of chitin, the homopolymer of N-acetyl-D-glucosamine, and of chitosan leads to the formation of glucosamine, the principal precursor of the sugars involved in the synthesis of glycosaminoglycans.
Chitosan has recognized film-forming, reconstituting, antibacterial, antifungal and wound-healing properties which have led to its use in medicine, in particular as a constituent of biomaterials intended to be used in orthopedic, plastic and reconstructive surgery, either as artificial skin, or as matrix capable of allowing bone, nerve or skin cells to become regenerated. These uses are for example described in U.S. Pat. No. 5,166,187 and in international application No. WO 96/02259.
Recently, DENUZIERE et al. (Electrophoresis, 1997, 18, 745-750) have shown, in vitro, that chitosan protected, at a physiological pH, chondroitin sulfates from hydrolysis when these sulfates were complexed beforehand, in aqueous medium, with chitosan.
Chitosan, its salts and its derivatives are defined in greater detail in many books, in particular in the book by MUZZARELLI entitled xe2x80x9cThe Polysaccharidesxe2x80x9d (1985) Academic-Press.
However, the Inventors have observed that the combination of a chondroitin sulfate or of a salt thereof with either chitosan or a salt or a derivative thereof, or alternatively a salt of such a derivative, makes it possible, unexpectedly, to obtain compositions which exhibit a therapeutic effect/dose of chondroitin sulfate ratio markedly greater than that exhibited by the compositions provided in U.S. Pat. No. 5,364,845, U.S. Pat. No. 5,587,363 and EP-A-0 693 928.
Thus, for chondroitin sulfate doses administered which are equivalent, or even lower, compositions comprising both chondroitin sulfate (or a salt of such a sulfate) and chitosan (or a salt, a derivative or a salt of a derivative of chitosan) have been found to improve more rapidly the clinical signs than the composition provided in the abovementioned state of the art; in particular, the compositions prepared by the Inventors have shown that they made it possible to reduce more rapidly the symptoms of pain and to improve mobility more quickly, as well as the tolerance to exercise.
The present invention therefore relates to the use of a preparation comprising:
a) from 1 to 50% by weight, relative to the total weight of the preparation, of at least one compound chosen from chondroitin sulfates and their salts, and
b) from 1 to 66% by weight, relative to the total weight of the preparation, of at least one compound chosen from chitosan, its salts, its derivatives and the salts of these derivatives, for the preparation of a composition for the prevention or treatment of rheumatic conditions by the general route.
For the purposes of the present invention, the expression xe2x80x9cgeneral routexe2x80x9d is understood to mean any route for administration of the composition allowing systemic distribution of the active ingredients which it contains, that is to say the enteral (oral and rectal) route, the parenteral (intramuscular, intravenous and subcutaneous) route and the transdermal route, excluding any in situ application of said composition.
According to a first preferred feature of the invention, the preparation comprises a sodium chondroitin sulfate.
According to another preferred feature of the invention, the preparation comprises a compound chosen from chitosan, its salts of adipic acid, ascorbic acid, formic acid, glycolic acid and lactic acid, N-acylchitosans, N-carboxyalkylchitosans, N-carboxy-acylchitosans, O-carboxyalkylchitosans, deoxyglycit-1-ylchitosans, hydroxyalkylchitosans and their salts obtained by addition with organic or inorganic acids.
Preferably, the chitosan is obtained by N-deacetylation of at least 80% of the chitin and is chosen from those provided by the Japanese companies KOYO, reference SK-400F80 or SK-50SEP with a deacetylation greater than 85%, KATAKURA, reference CTA-1 or CTA-2 with a deacetylation greater than 90% for the first and greater than 80% for the second, YAIZU, reference LL or LL-40 with a deacetylation greater than 80%, KYOWA, reference HW with a deacetylation greater than 85%.
Advantageously, the preparation comprises, furthermore, an effective quantity of one or more inhibitor of free radicals which participate in the processes for the protection, treatment and reconstitution of the connective tissues.
There may be mentioned, by way of examples of anti-free radicals capable of being used in the compositions, vitamin E and its derivatives, vitamin C and its derivatives (in particular manganese ascorbate and/or glucosamine ascorbate), bioflavanoids, superoxide dismutase and its salts, and extracts of plants known to exhibit anti-free radical effects, such as rosemary essential oil.
Advantageously, the preparation also comprises any component facilitating or participating in the biosyntheses or in the processes for the protection, treatment and reconstitution of the connective tissues, such as trace elements in organic or inorganic forms (manganese, copper, iron, zinc and the like), vitamins and nutrients.
In accordance with the invention, the preparation is capable of being used to prepare a pharmaceutical composition, in which case the latter is preferably formulated to be administered by the oral route.
As a variant, the preparation may also be used to prepare a dietary supplement capable, upon daily administration or as a cure in the form of a dietary supplement, of preventing or of treating rheumatic conditions.
The pharmaceutical composition or the dietary supplement thus prepared are capable of being provided in various forms suitable for oral administration: solid (tablets, gelatin capsules, lozenges to be chewed, granules, powders for oral suspension, and the like), pasty or liquid (syrups, oral solutions or suspensions, and the like). Accordingly, the preparation is capable of comprising, in addition, various additives (binding agents, diluents, lubricants, flow-enhancing agents, colorings, taste-enhancing agents, solvents and the like) which are chosen according to the form which it is desired to give the pharmaceutical composition or the dietary supplement.
The composition prepared according to the invention, whether it be pharmaceutical, or whether it be a dietary supplement, preferably comprises quantities of chondroitin sulfate and of chitosan which make it possible to provide, per kg of live weight and per day:
a) from 5 to 25 mg of sodium chondroitin sulfate, and
b) from 5 to 50 mg of chitosan, and this being in one or more doses.
In a particularly preferred manner, this composition comprises quantities of chondroitin sulfate and of a chitosan having a degree of N-deacetylation at least equal to 80%, making it possible to provide, per kg of live weight and per day:
a) from 10 to 20 mg and, preferably, about 15 mg of sodium chondroitin sulfate, and
b) from 10 to 20 mg and, preferably, about 15 mg of chitosan, in one or more doses.
It is capable of being used both in animals and in humans in the prevention and treatment of any rheumatic pathologies, whether they are of inflammatory, metabolic or degenerative origin, chronic or acute.
By way of examples of such pathologies, there may be mentioned arthritis, rheumatoid arthritis, ankylosing spondylarthritis (or related syndromes such as Fiessinger-Leroy-Reiter syndrome, arthropatic psoriasis), scapulohumeral periarthritis, tendinitis, bursitis, osteoarthritis (cervical osteoarthritis, vertebral osteoarthritis, coxarthrosis, and the like) and gout.
The following example is intended to illustrate the invention without however limiting its scope.